Hypoxia-induced epigenetic silencing of polo-like kinase 2 promotes fibrosis in atrial fibrillation

Abstract

AbstractFibrosis and inflammation promote atrial fibrillation (AF) and worsen its clinical outcome. The underlying molecular mechanisms, that are relevant for effective antifibrotic drug development, are still under debate. This study deciphers a novel mechanistic interplay between polo-like kinase 2 (PLK2) and the pro-inflammatory cytokine osteopontin (OPN) in the pathogenesis of atrial fibrosis. Compared to sinus rhythm (SR) controls, right atrial appendages and isolated right atrial fibroblasts from AF patients showed downregulation ofPLK2mRNA and protein levels, which were accompanied by remarkable hypoxia-sensitive DNA-methylation of thePLK2promotor. In an experimental setting, both, genetic deletion and pharmacological inhibition of PLK2 induced myofibroblast differentiation and reduced fibroblast proliferation. Notably, proteomics fromPLK2-deleted fibroblasts revealedde novosecretion of OPN. Accordingly, we observed higher OPN plasma levels in AF patients with atrial fibrosis compared to non-fibrosis AF patients. Hence, we provide evidence for PLK2 reactivation and/or OPN inhibition as potential novel targets to prevent fibrosis progression in AF.